Manufacture of pregnanes



Patented Apr. 6, 1954 UNITED STATES PATENT OFFICE MANUFACTURE .OF PREGNANES No Drawing. Application June 26, 1950, Serial No. 170,462

Claims priority, application Switzerland July 15, 1949 10 Claims.

This invention provides a process for the manufacture of 20-keto-pregnanes from pregnanyl- (20) -a1kyl-ketones having in the l'l-position the side chain It is known that cyclic-aliphatic ketones can be oxidized by means of per-acids to the corresponding acyloxy compounds. On the other hand, by the oxidation of dialkyl ketones with per-acids, there are obtained peroxides and no acyloxy-cornpounds. It would, therefore, be expected that pregnany1-(20) -ketones, in which the keto group is in an aliphatic side chain, would yield peroxides by oxidation with per-acids.

According to the present invention, there can unexpectedly be obtained from pregnanyl-(20)- alkyl-ketones in excellent yield ZO-acyloxy-pregnanes and from the latter by further oxidation ZO-keto-pregnanes, by oxidizing the starting material, if desired with temporary protection of any double bonds present, with a per-acid, and, if desired, hydrolyzing the resulting ZO-acyloxycompound and further oxidizing the product to a 2Q-oxo-pregnane.

The present process is of great importance since it is the best method for producing 20-oxypregnanes and from the latter 20-keto-pregnanes by starting from compounds of the bisnoroholanic acid series, and especially A -3-oxybisnor cholanic acid. The most productive known method, for example, starting from 3- acetoxy-A -bisnor cholanic acid and subjecting it to degradation by way of the azide gives a 32 per cent by weight yield of progesterone. On the other hand, by the process of the present invention the same starting material can easily be converted into progesterone with a total yield of about 50 per cent by weig'HtT The pregnanyl-(20)-alkyl-ketones, advantageously the -methyl-ketones, used as starting materials may contain in the steroid residue, especially in the 3-, 7-, 11- and/or IZ-position, a free or substituted hydroxyl group such as an acyloxy group, for example, an acetoxy, propionoxy or benzoyloxy group, or in the 11- position a keto group, or in the steroid ring, for instance, in the 5.6 or 11.12-position, a carbonto-carbon double bond.

The oxidation of the present invention is carpresence of an acid catalyst, such as sulphuric acid, perchloric acid or para-toluene sulphonic acid, the oxidation may be carried out without such a catalyst. Thus, for example, when it is desired to oxidize the free hydroxyl group to a keto group in a 3-hydroxy-pregnanyl-(20)- ketone with simultaneous degradation of the side chain, the oxidation is conducted Without the addition of a catalyst. It has been found that free hydroxyl groups can be oxidized to keto groups in the present process without the addition of acid. As a solvent there may be used an inert organic solvent, such as a halogenated hydrocarbon, especially chloroform, or ether. When the starting materials contain carbon-to-carbon double bonds, the latter are protected before the reaction with the per-acid. This is done with advantage by the addition of a halogen or a hydrogen halide, and especially by the addition of bromine. After the oxidation, the halogencompounds are dehalogenated in known manner, for example, by treatment with zinc in glacial acetic acid. ZO-acyloxy-pregnanes may be hydrolyzed to ZO-hydroxy-pregnanes, and may be further oxidized. As oxidizing agents there may be used, for example, chromium trioxide, permanganates or metal alcoholates or phenolates together with ketones, such as aluminum isopropylate in the presence of cyclohexanone. In order to convert a 3,20-dihydroxy-A -pregnene into a 3,20-dioxo-A -pregnene it is of advantage first to oxidize, for example, with cyclohexanone in the presence of aluminum isopropylate, whereby the 3-hydroxy-A -grouping is converted almost quantitatively into the 3-oxo-A -grouping. Should the less reactive hydroxyl group in the 20-position not have been attacked or have been attacked only partially, it can be subsequently converted also into a keto group, for example, by means of chromic acid.

The products of the invention are useful as medicaments or as intermediate products for making medicaments.

The following examples illustrate the invention, the percentages and parts being by weight unless otherwise stated, arid the relationship of parts by weight to parts by volume being the same as that of the gram to the cubic centimeter.

EXAMPLE 1 A -pregnene-3fi,2Ou-diOZ-diacetate CH3 CH3 HCOAc AcO- form containing 1.5 parts of perben z oic acid and then with 0.85 part by volume or a solution of 10 per cent. strength of sulphuric acid in glacial acetic acid. The reaction solution is allowed to stand, while the ice slowly melts,..-for.-. 12 daysat room temperature in the dark. It is then mixed with water and ether. The etherealsolution is washed once each with-water, sodium bicarbonate solution. and. water, driedand. .evaporated under reduced pressure at, room temperature. For the purpose .ofd bromination the residue is elr i n-rwm ri 'wmmw laci aq acid, and lqi parts of dust-are added inpor tions'imthe qurse one. hour, while stirring 4 110.111? t re glie h sret ee l g e r-eti c The whole s thenheated 120.75? C. in the..course of /4 l'1'o'ur. After. the, .a ddition of a water and ether, the; etherealsol' ition is washedwith water, dilute sgg ggngcartp ap solution. and water, dried and.. e vaporated. Th residue is}'reorystallized fronini ethanol to yield Ai-pregneneapzouim-deem .matineewe c.-

i h x datie 3? ifile r x esne (20) memen o with monoperphthalicacid and usinf' melting, at 159.5;1605", C.

The Y latter monoa cetate also obta ined from enfifi ig-ci bk ie e ae b oilin for 15 minutesla solution, of 1 ,part of. the;idiac etate and r O i s 'iuli exbonat n... Q-p rt by volume of, methanol andsz parts byvolume of Water.

0.6 part or the monoacetateand pgmpart of aluminum isopropylate 1 inbe parts by volume of toluene and QpartsbyVolume of cyolohexanone ar boiled for 40 minutes a current of .nitrogen under reflux. Thereis obtained .A -3 ketop snenerzq o'liacetat of th formula CHySJHs;

melting at 137.5-{138.5 C.

By oxidizing :35 hydroxy pregnanyl (20) methyl-ketone in an analogous manner with perbenzoic acid in the presence of sulfuric acid, pregnane-3B,20b-diol-zo-monoacetate of melting point 169-170 C. is formed;

4 EXAMPLE 2 1.46 parts of the diacetate obtained as described-inl lxample l are boiled under reflux with 60 parts by volume of a solution of 5 per cent. strength of caustic potash in methyl alcohol for one hour in a ciL'rent, of nitrogen. After the addition of ether and Water, the ethereal solution is washed with water, dried and evaporated. By recrystallizing the residue from methanol,

there is obtained 'A -pregnene-3p20e-diolof the formula CH3 CH3 melting at 177-178" C. The mother liquor is united With the residue from the evaporation of the mother liquor ofithe diacetate from Example 1, which has been hydrolyzedin thesame manner with 20 parts by volume ofa solution of 5 per cent. strength of-caustio potash in methyl alcohol. By chromatography over aluminum oxide, further quantitiesor-the diol ar obtained.

2 parts by volume of solvent are distilled off from a solution of 02 part of A5-pregnene3c,20adiol in 15 partsby volume of .toluene and 3 parts by volume of cyclohexanone. At intervals of '5 minutes, 3 additions of 0.05 part of aluminum isopropylate dissolvedin 1 part by volume of toluene are made. During the period of these additions, a further 1 part by volume of solventis distilled ofi. Then the whole is heated at the boil for one hour in acurrent of nitrogen, another 1.5 parts by volume distilling over. After the addition of water and ether, the ethereal solution is washed with dilutehydroohloric acidand water, dried and evaporated. In order toremove toluene and cyclohexanone, the residue is subjected to steam;distillation. The product is then sublimed at 120 C. in a high vacuum, and chromatographed over 6- parts of aluminum oxide. From the benzene-petroleum ether elutriates, there is obtained progesterone melting at .125- 126 C. after recrystallization from a mixture of ether and petroleum ether.

The benzene and benzene-ether elutriates contain A -3-keto-pr.egnene20a-ol of the formula CH: CH:

boiling for '25 minutes a solution 015 0.14 part of A -3-keto-pregnene-20a-ol-acetate and 0.07 part of potassium hydroxide in 4.2 parts by volume of methanol.

For conversion into progesterone all the fractions containing the keto-alcohol (0.07 part) are united and dissolved in 1 part by volume of carbon tetrachloride and 2 parts by volume of glacial acetic acid of 95 per cent. strength. A solution of 0.03 part of chromic acid in 1 part by volume of glacial acetic acid of 95 per cent. strength is then added while cooling with ice. The whole is allowed to stand first for 15 minutes in icewater and then for one hour at room tempera ture. After the addition of an aqueous solution of sodium sulphite, the whole is mixed with water and ether. The ethereal solution is washed, dried and evaporated, and the residue is united with the mother liquor remaining from the recovery of the progesterone described above. The mixture is then dissolved in 50 parts by volume of benzene free from thiophene and extracted by agitating 12 times with 5 parts by volume of sulphuric acid of 50 per cent. strength by volume. The sulphuric acid extracts are immediately diluted with water to ten times their volume, and extracted by agitation with ether. The ethereal solution is washed, dried and evaporated, and the is obtained, which melts at 1375-1385 C. The latter compound, after protection of the double bond with bromide, is oxidized with chromic acid and debrominated with zinc in glacial acetic acid to convert it into .A -pregnene-Bfi-ol-ZO-one acetate of the formula CH1 on, om 1 AcO it melts at '145145.5 C.

EXAMPLE 3 A -pregnene-3p,2OB-diol-ZO-monoacetate cm om Ac0- -n diol-20-monoacetate melting at 179-180 C.

The above monoacetate can also be obtained from A5 3s hydroxy-iso-pregnenyl (20) -methyl ketone by oxidation with monoperphthalic acid and para-toluene sulphonic acid with intermediate protection of the double bond with bromine.

0.15 part of the monoacetate, 1 part by volume of pyridine and 0.75 part by volume of acetic anhydride are allowed to stand at room temperature for 4 hours. pregnene-Bfi, 20,8-diol diacetate, melting at -126 C. and having the formula CH: CH]

Ac0- H is obtained.

By boiling a solution of 0.12 part of the monoacetate with 0.09 part of aluminum isopropylate in 12 parts by volume of toluene and 2 parts by volume of cyolohexanone for 30 minutes, there is obtained A -3-keto-pregnene-20p-ol acetate of the formula cm on.

melting at 159-1595 C. By boiling 0.06 part of the latter acetoxy-ketone with 0.03 part of potassium hydroxide in 1.8 parts by volume of methanol for hour, there is obtained A -3-ketopregnene-ZOB-ol of the formula melting at I'M-172 C.

The latter ketol can also be obtained by first converting 0.2 part of A -pregnene-3p,20p-diol- 20-monoacetate or the corresponding diacetate by boiling with 0.6 part of caustic potash solution ans-coo melting at 200.5-201.5 0., and thenpartially oxidizing the latter in the- 3-posi=tion with aluminum isopropylate-and cyclohexanone.

diol with 10 partsbyvolumeof glacial acetic acid for 2 hours in a current ofnitrogen-under reflux melting at l64.5-165.5.C.*.'Ihe latter compound, after intermediate protection of; the double bond with bromine, is converted by oxidation with chromic acid into A -pregnene-3,9-ol-20-one acetate.

EXAMPLE 4 Progesterone CH3 CH3 o 0.055 part of bromine, dissolved in 0.35 part by volume of carbon tetrachloride, is added to a solution, cooled with ice, of 0.11 part; of A -pregnene- 35,205-dio1 in 3 parts by volume of chloroform.

and 6 parts by volume of glacial acetic acid of 95 per cent. strength. Then 0.08 part of chromic acid in 3 parts by volume of glacial acetic acid of 95 per cent. strength is added-while cooling withice. The solution is allowed-to stand at room temperature for 110111. It is: then. cooledtwith ice-water and mixed with an. aqueous. solution of sodium sulphite. Afterthe addition of ether and water, the ethereal solution is washed with a dilute sodium carbonate solution and water,

dried and evaporated under reduced pressure at 35 C. For the purpose of debromination, the residue is dissolved-in 10 parts by volume of glacial acetic acid and heated up to 50 C. in the course of hour with the addition of 1 part of,

zinc dust. The whole is then heated up to 75 C. in the course of a further hour. After the addition of water and ether the ethereal solution is washed with dilute sodium carbonate solution and water, dried, and evaporated. The residue,

. cooling with ice.

, 9-0.4 pa t of -M-Sfi e Q-PWmene-Wmo1.is..diso ved nst p y v lume of. carbontetrach ori and 2 parts byvolume oiyglacial; aceticacid'. of

per cent. strength. 0.02 part of chromium trioxicle in 1. part by volume, of,glacial. acetic acidot95 per cent.,str ength is thenadded while The solution is allowed, to stand in ice-water for15-minutesand for 1 hour at15? C. After the, addition, of anaqueoussolul0.

tion of usodium sulphite, thewhole ismixed with water. and ether. The, ethereal solution iswashed with water, dilutesodium carbonate solution and water, the solution. is evaporated, and the-residue isdistilled under. a highvacuum at. -120 C. By recrystallizing thedistillate vfrom a mixture of ether and; petroleum ether, progesterone is obtained.

Having thus disclosed the invention, what is claimed is:

1. A process for-the preparation of a pregnane, which comprises. subjecting; a ,pregnanyl-izmlower alkyl-ketoneto thezaction of aper-acid selected from thegroup consisting. of perbenzoic acid, and monoperphthalic acid, and separating .theresulting corresponding 20-acyloxy compound.

2. A, process forthe-preparationv of a;pregnane, which comprises subjecting a nuclearly-saturated pregnanyl-(20) -.lower: alkyl-ketone to, the, action of a per-acid selected; from the, group consisting of perbenzoic; acidandmonoperphthalic acid,,and separating the resultingcorresponding 20-acyloxy compound.

3. A process for thefpreparation of apregnane, which comprises subjectinga A -3,-acyloxy-preg- .nenyl-(20)dowenalkyl-ketone to the action of a per-acidselected from the, group consisting of perbenzoic acidv and monoperphthalic acid, with intermediate protection of the double bond, and separatingthe resulting corresponding 20- acyloxy compound.

4. A process for the preparation of progesterone, which comprises subjecting 3-acetoxy-A pregnenyl-(20) -methy;l-ketone adibromide to the action of perbenzoic acid whereby the A- -pregnene-3,20-diol-diacetate ,dibromide'is produced, treating the latter with a debrominating agent to produce the M-pregnene-3,20-diol-diacetate, then treating the last-named compound with a saponifying agent to produce the A -pregnene- 3,20-diol-,; subjecting the latter tooxidation by means-of aluminum isopropylate in presence of a ketone, and then treating the resultant'product, wherein the 20-hydroxy group is still partly unattacked, with chromic' acid whereby the 20- hydroxy group -is. converted into the 20-keto group.

5. A process for the preparation of a pregnane, which comprises subjecting a pregnanyl-(20)- lower alkyl-ketone to the action of perbenzoic acid, and separating the resulting 20-acyloxy pregnane compound.

6. A process for thepreparationof-atpregnane, which comprises subjectinganuclearly saturated pregnanyl-(20) -lower alkyl ketone to the action of perbenzoic acid.

'7. A processfor the preparation of a pregnane, which comprises, subjecting a A -3-acyloxy-pregnenyl-(20)-lower alkyl-ketone to the action of perbenzoic acid,with intermediate protection of the double bond.

8. A process for the. preparation of progesterone, which comprisessubjecting 3-acetoxy-A pregnenyl-20-methyl ketone dibromide to the action of perbenzoic acid, whereby the A -pregnene- 10 pregnanyl-(ZO) -lower alkyl ketones and their 3- acyloxy derivatives to the action oi! perbenzoic acid.

References Cited in the file of this patent UNITED STATES PATENTS Number Name Date 2,304,836 Marker Dec. 15, 1942 2,341,557 Julian Feb. 15, 1944 OTHER REFERENCES Sarett: Jour. Am. Chem. Soc. 69, 2899-2901 (1947). 

1. A PROCESS FOR THE PREPARATION OF A PREGNANE, WHICH COMPRISES SUBJECTING A PREGNANYL-(20)LOWER ALKYL-KETONE TO THE ACTION OF A PER-ACID SELECTED FROM THE GROUP CONSISTING OF PERBENZOIC ACID AND MONOPERPHTHALIC ACID, AND SEPARATING THE RESULTING CORRESPONDING 20-ACYLOXY COMPOUND. 